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Title
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Inhibitory actions of the NRG-1/ErbB4 pathway in macrophages during tissue fibrosis in heart, skin and lung
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Author
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Abstract
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| The neuregulin-1 (NRG-1)/ErbB system is an endothelium-controlled paracrine system modulating cardiac performance and adaptation. Recent studies indicate that NRG-1 has anti-fibrotic effects in the left ventricle (LV), which were explained by direct actions on cardiac fibroblasts. However, the NRG-1/ErbB system also regulates the function of macrophages. In this study, we hypothesized that the anti-fibrotic effect of NRG-1 in the heart is at least partially mediated through inhibitory effects on macrophages. We also hypothesized that the anti-fibrotic effect of NRG-1 may be active in other organs, such as skin and lung. First, in a mouse model of angiotensin II (ATII)-induced myocardial hypertrophy and fibrosis, NRG-1 treatment (intraperitoneal; 20µg.kg-1.day-1) significantly attenuated myocardial hypertrophy and fibrosis and improved passive ventricular stiffness (4 weeks). Interestingly, 1 week after exposure to ATII, NRG-1 already attenuated myocardial macrophage infiltration and cytokine expression. Furthermore, mice with myeloid-specific deletion of the ErbB4 gene (ErbB4F/FLysM-Cre+/-) showed an intensified myocardial fibrotic response to ATII. Consistently, NRG-1 activated the ErbB4 receptor in isolated macrophages, inhibited PI3K/Akt and STAT3 signaling pathways and reduced the release of inflammatory cytokines. Further experiments showed that the anti-fibrotic and anti-inflammatory effects of NRG-1 were reproducible in mouse models of bleomycin-induced dermal and pulmonary fibrosis. Overall, this study demonstrates that the anti-fibrotic effect of NRG-1 in the heart is linked to an anti-inflammatory activity NRG-1/ErbB4 signaling in macrophages. Secondly, this study shows that NRG-1 has anti-fibrotic and anti-inflammatory effects in other organs than the heart, such as in skin and lung. |
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Language
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English
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Source (journal)
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American journal of physiology : heart and circulatory physiology / American Physiological Society. - Bethesda, Md, 1977, currens
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Publication
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Bethesda, Md
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2017
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ISSN
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0363-6135
[print]
0363-6135
1522-1539
[online]
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DOI
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10.1152/AJPHEART.00206.2017
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Volume/pages
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313
:5
(2017)
, p. H934-H945
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ISI
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000416503900009
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Pubmed ID
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28822966
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Full text (Publisher's DOI)
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Full text (open access)
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